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Heterozygous gain of function mutations in the ZIC1 gene have been described with syndromic craniosynostosis, variable cerebral or cerebellar abnormalities and mild to moderate developmental delay. Deletion of chromosome 3q25.1 including both adjacent ZIC1 and ZIC4 genes have been described as a cause of variable cerebellar abnormalities including Dandy-Walker malformation. We report two siblings presenting with neonatal microcephaly, agenesis of the corpus callosum, brachycephaly with reduced volume of the posterior fossa, cerebellar and pons hypoplasia, scoliosis and tethered cord (closed neural tube defect). One of the siblings had apparent partial rhombencephalosynapsis. Trio analysis of exome sequencing data revealed a novel heterozygous frameshift mutation in ZIC1 at the end of exon 3 in one sibling and was confirmed by Sanger sequencing in both children. The mutation was not detected in DNA of both parents, which suggests parental gonadal mosaicism. We show that expression of the mutant allele leads to synthesis of a stable abnormal transcript in patient cells, without evidence for nonsense-mediated decay. Craniosynostosis was not present at birth, which explains why ZIC1 mutations were not initially considered. This severe brain malformation indicates that premature closure of sutures can be independent of the abnormal brain development in subjects with pathogenic variants in ZIC1., (Copyright © 2018. Published by Elsevier Masson SAS.)

Objective: Children with syndromic craniosynostosis are at risk of intracranial hypertension. This study aims to examine patient profiles of transcranial Doppler (TCD) cerebral blood flow velocity (CBFv) and systemic blood pressure (BP) in subjects with and without papilledema at the time of surgery, and subsequent effect of cranial vault expansion., Methods: Prospective study of patients treated at a national referral center. Patients underwent TCD of the middle cerebral artery 1 day before and 3 weeks after surgery. Measurements included mean CBFv, peak systolic velocity, and end diastolic velocity; age-corrected resistive index (RI) was calculated. Systemic BP was recorded. Papilledema was used to indicate intracranial hypertension., Results: Twelve patients (mean age 3.1 years, range 0.4-9.5) underwent TCD; 6 subjects had papilledema. Pre-operatively, patients with papilledema, in comparison to those without, had higher TCD values, RI, and BP (all p = 0.04); post-operatively, the distinction regarding BP remained (p = 0.04). There is a significant effect of time following vault surgery with a decrease in RI (p < 0.01)., Conclusion: Patients with syndromic craniosynostosis who have papilledema have a different TCD profile with raised BP. Vault surgery results in increased CBFv and decrease in RI, however the associated systemic BP response to intracranial hypertension remained at short-term follow-up., (Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance.

Object: Craniosynostosis syndromes are characterized by prematurely fused skull sutures, however, less is known about skull base synchondroses. This study evaluates how foramen magnum (FM) size, and closure of its intra-occipital synchondroses (IOS) differ between patients with different craniosynostosis syndromes and control subjects; and whether this correlates to ventriculomegaly and/or Chiari malformation type I (CMI), intracranial disturbances often described in these patients., Methods: Surface area and anterior-posterior (A-P) diameter were measured in 175 3D-CT scans of 113 craniosynostosis patients, and in 53 controls (0-10 years old). Scans were aligned in a 3D multiplane-platform. The frontal and occipital horn ratio was used as an indicator of ventricular volume, and the occurrence of CMI was recorded. Synchondroses were studied in scans with a slice thickness ≤1.25 mm. A generalized linear mixed model and a repeated measures ordinal logistic regression model were used to study differences., Results: At birth, patients with craniosynostosis syndromes have a smaller FM than controls (p < 0.05). This is not related to the presence of CMI (p = 0.36). In Crouzon-Pfeiffer patients the anterior and posterior IOS fused prematurely (p < 0.01), and in Apert patients only the posterior IOS fused prematurely (p = 0.028)., Conclusion: The FM is smaller in patients with craniosynostosis syndromes than in controls, and is already smaller at birth. In addition to the timing of IOS closure, other factors may influence FM size., (Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: Patients with craniosynostosis syndromes are at risk of increased intracranial pressure (ICP) and Chiari I malformation (CMI), caused by a combination of restricted skull growth, venous hypertension, obstructive sleep apnea (OSA), and an overproduction or insufficient resorption of cerebrospinal fluid. This study evaluates whether craniosynostosis patients with CMI have an imbalance between cerebellar volume (CV) and posterior fossa volume (PFV), that is, an overcrowded posterior fossa., Methods: Volumes were measured in 3D-SPGR T1-weighted MR scans of 28 'not-operated' craniosynostosis patients (mean age: 4.0 years; range: 0-14), 85 'operated' craniosynostosis patients (mean age: 8.0 years; range: 1-18), and 34 control subjects (mean age: 5.4 years; range: 0-15). Volumes and CV/PFV ratios were compared between the operated and not-operated craniosynostosis patients, between the individual craniosynostosis syndromes and controls, and between craniosynostosis patients with and without CMI. Data were logarithmically transformed and studied with analysis of covariance (ANCOVA)., Results: The CV, PFV, and CV/PFV ratios of not-operated craniosynostosis patients and operated craniosynostosis patients were similar to those of the control subjects. None of the individual syndromes was associated with a restricted PFV. However, craniosynostosis patients with CMI had a significantly higher CV/PFV ratio than the control group (0.77 vs. 0.75; p = 0.008). The range of CV/PFV ratios for craniosynostosis patients with CMI, however, did not exceed the normal range., Conclusion: Volumes and CV/PFV ratio cannot predict which craniosynostosis patients are more prone to developing CMI than others. Treatment should focus on the skull vault and other contributing factors to increased ICP, including OSA and venous hypertension., (Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: Little is known about the long-term prevalence of elevated intracranial pressure (ICP), obstructive sleep apnoea (OSA), level of education, language and motor skills, impaired sight and hearing in craniosynostosis syndromes. The objective of this study was to define the prevalence per syndrome of elevated ICP, OSA, impaired sight and impaired hearing., Methods: A retrospective study was undertaken on 167 consecutive patients diagnosed with Apert, Crouzon, Pfeiffer, Muenke or Saethre-Chotzen syndrome, aged 1-25 years and treated between 1983 and 2008. The mean age at time of referral and review was 1 years and 2 months and 10 years and 3 months, respectively., Results: Patients with Apert and Crouzon/Pfeiffer syndromes had the highest prevalence of elevated ICP (33% and 53%, respectively) and OSA (31% and 27%, respectively), while Saethre-Chotzen syndrome was also associated with a fair risk for elevated ICP (21%). The prevalence of impaired sight (61%) and hearing (56%) was high in all syndromes., Conclusion: Based on these data, a syndrome-specific risk profile with suggestions for screening and treatment is presented., (Copyright 2009 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

A 10-year-old girl with Apert syndrome underwent a Le Fort III osteotomy with the positioning of internal and external distraction devices. The operation was straightforward with no intraoperative complications. Very soon after completion of surgery an anisocoria (unilateral dilation of a pupil) was noticed. This was followed by intracranial oedema which was fatal. The aetiology was dissection of the right internal carotid artery is reported. The complications of Le Fort osteotomies are discussed regarding patients with complex syndromal craniosynostosis and midface hypoplasia, such as Apert syndrome., (Copyright © 2010 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

We report a case of a girl who presented with typical absence seizures at age of 4.5 years. EEG showed absence seizures of sudden onset with 3 Hz spike-and-waves that also correlated with the clinical absences. The seizure semiology included subtle deviation of the eyes which prompted MRI investigation of the brain. This showed a periventricular nodular heterotopia in the mid to anterior horn of the right lateral ventricle. Although possibly coincidental, periventricular heterotopia are considered to be epileptogenic and this association has been reported once before. Migration disorders, such as in the periventricular heterotopia of our patient, may influence the formation and excitability of the striato-thalamo-cortical network involved in the generation of 3 Hz spike-waves., (2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Neonatal stroke occurs in 1 in 2300-5000 live births, the incidence of which is lower than that in adults, but still higher than that in childhood. The higher incidence of perinatal stroke in preterm and term infants compared to stroke in childhood may be partly explained by higher detection rates using routine fetal ultrasound and postnatal cranial sonography. In addition, there is greater availability of magnetic resonance imaging (MRI) for neuroimaging in preterm and full-term infants, which is due in part to the availability of MR-compatible incubators and MR systems at or near the neonatal intensive care unit. In addition, the wide range of MR techniques, such as T2-, diffusion- and susceptibility-weighted imaging allows improved visualization and quantification of neonatal stroke or hypoxic-ischemic injury. This chapter reviews the MR neuroimaging modalities that actually assist the clinician in the detection of neonatal stroke.

Purpose: Triphalangeal thumb is characterized as a congenital difference of the thumb with an extra phalanx. Additional thumb length is attributed mostly to the extra phalanx. The influence of the epiphyseal plate positions on growth in congenital hand anomalies is unclear. The purpose of this article was to compare the length of the first metacarpal in triphalangeal thumbs with the length of the same bone in normal thumbs and to investigate the influence of the often aberrant metacarpal epiphyseal plates on the length of the triphalangeal thumb metacarpal during growth., Methods: The positions of the epiphyseal plate and the relative length of the first metacarpal were examined retrospectively in 37 patients with triphalangeal thumb. Ratios of the measurements were calculated (metacarpal II/metacarpal I) and compared with a normal population. Subjects were divided into 3 groups based on the position of the epiphyseal plate (double, proximal, distal)., Results: The distally placed growth plate was the most common variety, present in 22 of patients, followed by the proximal position in 14, and double epiphyseal plates in 6. All ratios of patients with triphalangeal thumb were significantly smaller than those of a normal population, indicating a longer first metacarpal in this condition. First metacarpals in triphalangeal thumb with double epiphyses grew disproportionately more than those of a normal population, whereas those with distal epiphyses grew disproportionately less than normal. First metacarpals with proximal epiphyses grew at the same rate as normal first metacarpals., Conclusions: In this study population the most common growth plate location was distal whereas the most common location in the normal population is proximal. The different positions of the epiphyseal plates correlate with growth differences in patients with triphalangeal thumb.